We propose to investigate, in experimental animals, the possibility that the excitatory amino acids (EAA), glutamate (Glu) and aspartate, may be responsible for a type of brain damage (anoxic/ischemic) that occurs perinatally in the human and constitutes a major cause of neuropsychiatric developmental disability. These compounds are major excitatory transmitters in the CNS and also have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, very recently, new classes of EAA antagonists were discovered which penetrate blood brain barriers. Several lines of evidence suggest that endogenous EAA may cause or that EAA antagonists can prevent brain damage associated with anoxia/ischemia. Such evidence derives from both in vitro and in vivo research. However, the in vivo evidence has a tenuous character because of inadequacies inherent in the animal models of anoxia/ischemia used. Moreover, it was generated in adult animal models that may not be entirely relevant to mechanisms operative in earlier life. The research proposed herein is aimed at clarifying the mechanism(s) of, and developing approaches for preventing, anoxic/ischemic neuronal degeneration in the developing CNS. The proposed research will be conducted with two models, one in vitro and one in vivo, which we have developed for the specific purpose of investigating the role of excitotoxic mechanisms in perinatal anoxic/ischemic neuronal degeneration. A major goal of the research is to test drugs that we find effective in preventing Glu-induced and ischemic neuronal degeneration in vitro for their ability to prevent hypoxic/ischemic brain damage in vivo in the 10 day old infant rat. We also will study the vulnerability of rat brain to hypoxic/ischemic damage in earlier post or prenatal stages of development, will evaluate whether this new rat model of perinatal brain damage is suitable for studying neurobehavioral consequences of such damage, and will investigate the ontogeny of EAA and related transmitter systems that may be important determinants of vulnerability to hypoxic/ischemic brain damage.